This application relates generally to medical systems and procedures and more particularly to systems and procedures for treating targeted tissues, e.g., cardiac tissue, of a living being and to medical instruments and methods of use to remove occlusive material from a vessel, duct or lumen within the body of a living being.
Cardiovascular disease is the leading cause of death in the industrial world today. During the disease process, atherosclerotic plaques develop at various locations within the arterial system of those affected. These plaques restrict the flow of blood through the affected vessels. Of particular concern is when these plaques develop within the blood vessels that feed the muscles and other tissues of the heart. In healthy hearts, cardiac blood perfusion results from the two coronary arterial vessels, the left and right coronary arteries that perfuse the myocardium from the epicardial surface inward towards the endocardium. The blood flows through the capillary system into the coronary veins and into the right atrium via the coronary sinus. When atherosclerosis occurs within the arteries of the heart it leads to myocardial infarctions, or heart attacks, and ischemia due to reduced blood flow to the heart tissues. Over the past few years numerous devices and methods have been evaluated for treating cardiovascular disease, and for treating the resulting detrimental effects that the disease has upon the myocardium and the other heart tissues. They are: traditional surgical methods (e.g. open heart surgery), minimally invasive surgery, traditional interventional cardiology (e.g. angioplasty, atherectomy, stents), and advanced interventional cardiology (e.g. catheter based drug delivery). Other recent advances in cardiovascular disease treatment involve transmyocardial revascularization (TMR), and growth factor and gene delivery.
Traditional methods for treating cardiovascular disease utilize open surgical procedures to access the heart and bypass blockages in the coronary blood vessels. These procedures require an incision in the skin extending from the supra-sternal notch to the zyphoid process, the sawing of the sternum longitudinally in half, and the spreading of the rib-cage to surgically expose the patient""s heart. Based upon the degree of coronary artery disease, a single, double, triple, or even greater number of vessels are bypassed. Each bypass is typically performed by creating a separate conduit from the aorta to a stenosed coronary artery at a location distal to the occluded site. In general, the conduits are either synthetic or natural bypass grafts. Grafting with the internal thoracic (internal mammary) artery directly to the blocked coronary site has been particularly successful with superior long-term patency results. During conventional cardiac surgery, the heart is stopped using cardioplegia solutions and the patient is put on cardiopulmonary bypass. The bypass procedure uses a heart-lung machine to maintain circulation throughout the body during the surgical procedure. A state of hypothermia may be induced in the heart tissue during the bypass procedure to preserve the tissue from necrosis. Once the procedure is complete, the heart is resuscitated and the patient is removed from bypass.
There are great risks associated with these traditional surgical procedures such as significant pain, extended rehabilitation time and high risk of mortality for the patient. The procedure is time-consuming and costly to perform. Traditional cardiac surgery also requires that the patient have both adequate lung and kidney function in order to tolerate the circulatory bypass associated with the procedure and a number of patients which are medically unstable are thus not a candidate for bypass surgery. As a result, over the past few years, minimally invasive techniques for performing bypass surgery have been developed and in some instances the need for cardiopulmonary bypass and extended recovery times are avoided. A number of companies, e.g., Heartport, Inc. of Redwood City, Calif. and Cardiothoracic Systems, Inc. of Cupertino, Calif., have developed devices that allow for cardiac surgical procedures that do not require a grossly invasive median sternotomy or traditional cardiopulmonary bypass equipment. The procedures result in a significant reduction in pain and rehabilitation time.
In addition, as an alternative to surgical methods, traditional interventional cardiology methods (e.g. angioplasty, atherectomy, and stents) non-surgical procedures, such as percutaneous transluminal coronary angioplasty (PTCA), rotational atherectomy, and stenting have been successfully used to treat this disease in a less invasive non-surgical fashion. In balloon angioplasty a long, thin catheter having a tiny inflatable balloon at its distal end is threaded through the cardiovascular system until the balloon is located at the location of the narrowed blood vessel. The balloon is then inflated to separate and expand the obstructing plaque and expand the arterial wall, thereby restoring or improving the flow of blood to the local and distal tissues. Stenting utilizes a balloon tipped catheter to expand a small coil-spring-like scaffold at the site of the blockage to hold the blood vessel open. Rotational atherectomy utilizes a similarly long and thin catheter, but with a rotational cutting tip at its distal end for cutting through the occluding material.
Catheter instruments have been suggested or disclosed in the patent literature for effecting non-invasive or minimally invasive revascularization of occluded arteries. For example, in U.S. Pat. No. 4,445,509 there is disclosed a recanalization catheter designed specifically for cutting away hard, abnormal deposits, such as atherosclerotic plaque, from the inside of an artery, while supposedly preserving the soft arterial tissue. That recanalizing catheter includes a sharp-edged, multi-fluted, rotating cutting tip mounted at the distal end of the catheter and arranged to be rotated by a flexible drive shaft extending down the center of the catheter. The rotation of the cutting head is stated as producing a xe2x80x9cdifferential cuttingxe2x80x9d effect, whereupon relatively hard deposits are cut away from relatively soft tissue. Suction ports are provided to pull the hard particles produced by the cutting action into the catheter for removal at the proximal end thereof so that such particles do not flow distally of the catheter where they could have an adverse effect on the patients"" body.
In U.S. Pat. No. 4,700,705, which is assigned to the same assignee as this invention and whose disclosure is incorporated by reference herein, there are disclosed and claimed catheters and methods of use for effecting the opening of a vessel, duct or lumen, such as the opening of a atherosclerotic restriction (partial or total occlusion) in an artery. These catheters are elongated flexible members of sufficient flexibility to enable them to be readily passed through the body of the patient to the situs of the atherosclerotic plaque in the artery to be opened. A working head is mounted at the distal end of the catheter and is arranged for high-speed rotation about the longitudinal axis of the catheter. In some embodiments the catheter may eject fluid at the working head to expedite the restriction-opening procedure.
In U.S. Pat. No. 4,747,821, which is also assigned to the same assignee as this invention and whose disclosure is incorporated by reference herein, there is disclosed and claimed other catheters particularly suited for revascularization of arteries. Each of those catheters includes a rotary working head having at least one non-sharp impacting surface to effect material removal without cutting. Moreover, those catheters are arranged to eject fluid adjacent the working head to expedite the revascularization procedure. In particular, the rotation of the working head produces a powerful, toroidal shaped vortex contiguous with the working head which has the effect of recirculating any particles that may have been broken off from the material forming the arterial restriction so that the working head repeatedly impacts those particles to reduce their size.
In U.S. Pat. No. 5,042,984, which is also assigned to the same assignee as this invention and whose disclosure is incorporated by reference herein, there are disclosed and claimed catheters whose working heads include impacting surfaces of differing aggressiveness which may be selectively brought into engagement with the restriction to be opened. Such catheters also make use of exiting jets of liquid as described above.
Other atherectomy devices for enlarging an opening in a blood vessel have been disclosed and claimed in the following U.S. Pat. No. 4,589,412 (which is assigned to the same assignee as this invention and whose disclosure is incorporated by reference herein); U.S. Pat. Nos. 4,631,052; 4,686,982 (which is assigned to the same assignee as this invention and whose disclosure is incorporated by reference herein); U.S. Pat. No. 4,749,376 (which is assigned to the same assignee as this invention and whose disclosure is incorporated by reference herein); U.S. Pat. Nos. 4,790,813; 5,009,659; 5,074,841; 5,282,484; 5,366,463; 5,368,603; 5,402,790; 5,423,742; and U.S. Pat. No. 5,429,436.
Some rotary atherectomy devices are in use in this country for revascularizing occluded arteries. However, their use is limited to some very selected applications. Thus, in many instances a vascular occlusion of a coronary artery can only be treated by coronary bypass surgery wherein a graft, e.g., a saphenous vein section and/or mammary artery section, is surgically shunted across the occluded coronary artery. Unfortunately a significant percentage of bypass surgical grafts become re-occluded over time. Thus, the re-occluded graft has to be either bypassed by another graft (i.e., second bypass surgery), or the re-occluded graft has to be revascularized (i.e., its lumen reopened) by some intravascular procedure. If the occluded graft is not totally occluded, balloon angioplasty may be indicated to reopen the graft. Where, however, the graft is totally occluded or heavily occluded by frangible deposits balloon angioplasty is unavailable. Thus, if revascularization of such a graft is desired, resort may be to rotary atherectomy.
One currently available rotary atherectomy device is the ROTOBLATOR(copyright) System of Heart Technology, Inc. That system utilizes a catheter having a diamond coated elliptical burr which is rotated at a high rate of speed, e.g., up to 190,000 rpm. The burr serves to break the atherosclerotic plaque into fine particles which are allowed to remain in the patient""s body for disposal by the patient""s reticuloendothelial system.
As is known to those skilled in the art, one problem with a rotary atherectomy device is that unless the debris produced is so small and benign that it can be left within the patient""s vascular system there must be some means to ensure that the debris does not flow upstream into the aorta during the procedure or into the downstream artery graft at the break-through point when the device comes out the distal side of a total occlusion, since either action could present a significant hazard to the patient. In particular, the former route risks stroke, the later route risks local ischemia of heart muscle when debris blocks off small arteries.
Thus, the collection and/or aspiration of debris produced during the revascularization of occluded arterial bypass grafts or other blood vessels is getting considerable attention in the medical arts. For example, Possis Medical, Inc., the assignee of U.S. Pat. Nos. 5,370,609 and 5,496,267, provides catheter devices designated as the ANGIOJET Rapid Thrombolectomy System and the ANGIOJET Rheolytic Thrombolectomy System. These devices are presumably constructed in accordance with those patents and are believed to be presently undergoing clinical trials. The catheter devices disclosed in those patents utilize high velocity jets of saline to abrade the blockage. In particular, the patents disclose utilizing the momentum of the saline jets to create a local vacuum to entrain any particulate material produced by the revascularization procedure, with the momentum and the local positive pressure being sufficient to carry the saline and debris to a return collection bag.
Another atherectomy device which is currently undergoing clinical trials is the Coronary TEC(copyright) System of Interventional Technologies, Inc. That device is believed to be the subject of U.S. Pat. No. 5,224,945, and basically comprises a catheter having a working head with microtome sharp blades for cutting plaque circumferentially. The excised plaque is extracted by suction through a central lumen in the catheter into an exteriorly-located vacuum bottle. No control of the quantity of flow of the debris-carrying fluid from the catheter is disclosed. U.S. Pat. No. 5,030,201 (Palestran) discloses a system including an expandable atherectomy catheter arranged to be rotated to cut through an occluded artery to revascularize it. The atherectomy catheter includes an expandable cutting head having plural elongated cutting members which are mounted on a flexible torque tube incorporating a vacuum or aspiration system for retrieval of excised material. The cutting head is arranged to be rotated to cause the elongated members to cut away atheromatous material or blood clots. The atherectomy catheter is arranged to be inserted into the blood vessel through a coaxial delivery catheter, also forming a part of the system. The mechanism for aspirating particles of atheromatous material or blood clots removed by the elongated cutting members is disclosed as being in the form of a vacuum port provided at the proximal end of either the delivery catheter, the atherectomy catheter or a xe2x80x9cretracting catheterxe2x80x9d which also constitutes a part of the system. Saline solution or some other irrigant is infused through one of the catheters of the device that is not being used for aspiration. The infusion rate of the saline solution is balanced with the aspiration rate to avoid any net removal of fluid from the vessel. In particular, the patent teaches that by balancing the infusion rate of the saline solution to the aspiration rate, the net removal of fluid from the vessel can be brought close to zero, thereby minimizing blood loss.
While the balancing of the infusion and aspiration flow rates to minimize blood loss may be desirable, such action does not insure positive removal of all debris produced during the revascularization procedure.
Accordingly, a need exists for apparatus and a method of use to revascularize partially or totally occluded blood vessels, while positively assuring that any particles produced during the revascularization procedure are removed from the patient""s body. In the case of partially or totally occluded coronary bypass grafts, a need exists for intravascular atherectomy apparatus and methods of use for effectively producing a lumen through the occlusion for the free flow of blood, without the risk that any debris produced during the lumen opening procedure will enter into the aorta or downstream of the occlusion once it has been crossed or opened.
While many patients are successfully relieved of their symptoms and pain with traditional interventional procedures, in a significant number of patients the blood vessels eventually restenose or reocclude within a relatively short period of time. As such, researchers have explored advanced interventional cardiology methods (e.g., catheter based drug delivery, radiation therapy, etc.) to delay or prohibit the process of restenosis. As summarized by Raoul Bonan, MD (xe2x80x9cLocal Drug Delivery for the Treatment of Thrombus and Restenosis, IAGS Proceedings, The Journal of Invasive Cardiology, 8:399-408, October 1996), the cardiology community has recently begun to augment standard catheter-based treatment techniques with devices that provide local delivery of medications to the treated site. These devices are disclosed in co-pending U.S. patent application Ser. No. 09/668,318, filed Sep. 22, 2000, entitled Systems and Methods for Delivering Beneficial Agents into Targeted Tissue of a Living Being, which is a Continuation-In-Part of U.S. patent application Ser. No. 09/368,410, filed on Aug. 5, 1999, entitled Systems and Methods for Delivering Agents into Targeted Tissue of a Living Being, which applications are assigned to the same assignee as this invention and whose disclosures are incorporated by reference herein. This localized administration of drugs has shown promise for counteracting clotting, reducing inflammatory responses, and blocking proliferative responses, such as intimal hyperplasia. Neointimal hyperplasia is the migration and proliferation of vascular smooth muscle cells leading to the deposition of extracellular matrix components at the injury site. It is believed that biological growth factors stimulate the vascular smooth muscle (VSM) cells to proliferate causing the intima to thicken. This intimal thickening narrows the lumen of the blood vessel and restricts blood flow.
The subject invention is well suited for localized administration of agents (e.g. drugs, biologicals) counteracting clotting, reducing inflammatory responses, and blocking proliferative responses, such as intimal hyperplasia. One such agent is a growth arresting lipid. Research by Charles C., Sandirasegarane L, Yun J, Bourbon N, Wilson R, Rothstein R, Levison S, Kester M. reported in the article Ceramide-Coated Balloon Catheters Limit Neoinitmal Hyperlasia After Stretch Injury in Carotid Arteries, Circulation Research. 2000;87:282 has shown that direct delivery of a cell-permeable growth-arresting lipid delivered via a balloon embolectomy catheter limits the extents of the neointimal hyperplasia after the balloon-induced stretch injury. It was shown that a sphingolipid-derived cell permeable ceramide can arrest the growth of smooth muscle cell pericytes in vivo without causing significant apoptosis.
Sphingolipids are membrane lipids that serve as a substrate for the formation of second messengers. Ceramide, a second messenger derived from cytokine receptor-activated sphingomyelin catabolism, stimulates differentiation, inhibits proliferation, and has been associated with apoptosis. Ceramide is an N acyl sphingosine, the lipid moiety of glycosphingolipids. Ceramides also are involved in the regulation of cellular proliferation and differentiation in a variety of cell types. Ceramide is considered to be a antineoplastic agent. Many studies have focused on ceramides and their sphingoid base metabolites as growth inhibitors. Glycosphingolipids are amphiphatic molecules consisting of a ceramide lipid moiety, embedded in the outer leaflet of the plasma membrane, linked to one of hundreds of different externally oriented oligosaccharide structures. They form cell type specific profiles which characteristically change in development, differentiation and oncogenic transformation, suggesting their implication in fundamental cellular processes including growth, differentiation, morphogenesis, cell to matrix interaction and cell to cell communication. Glycosphingolipids are believed to be integral components of the plasma membrane microdomains, known as rafts and caveolae. Furthermore, their biosynthesis has been shown to have a vital role for embryogenesis of mammals. In the last decade sphingolipid metabolites were recognized as bioactive molecules; whereas sphingosine and sphingosine-1-phosphate were found to be primarily mitogenic signals, ceramide appears to provide the breaks for unrestrained cell growth, being involved in apoptosis, differentiation and senescence.
The studies by Kester indicate that the ceramide penetrates into the intimal and medial layers of the VSM. The ceramide treatment decreases the number of vascular smooth muscle cells entering the cell cycle. Research indicates that the intercalation of ceramide into vascular smooth muscle cells correlated with rapid inhibition of trauma-associated phosphorylation of extracellular signal-regulated kinase and protein kinase B. In generic terms, the lipid blocks factor-mediated signaling cascades that reduces neointimal hyperplasia with minimal systemic complications.
Antineoplastic agents include a wide range of compounds that work by various mechanisms. By definition, anti neoplastic agents are agents that inhibit new growth. Examples of compounds considered to be antineoplastic agents are, alkylating agents, antimetabolites, antimitotic agents, antibiotics, hormones, enzymes, cytoprotective agents, biological response modifiers, and monoclonal antibodies.
The mechanism of action by which these agents suppress proliferation of neoplasms is that, generally, they affect one or more stages of cell growth or replication. Some agents are more active at one specific phase of cellular growth and are considered cell cycle specific agents. Those agents that are active on both proliferating and resting cells are considered cell cycle nonspecific agents.
Antineoplastic agents such as alkylating agents form highly reactive carbonium ions which react with essential cellular components, thereby altering normal biological function. Alkylating agents replace hydrogen atoms with an alkyl radical causing cross-linking and abnormal base pairing of DNA molecules. They also react with sulfhydryl, phosphate and amine groups resulting in multiple lesions in both dividing and non-dividing cells. The resultant defective DNA molecules are unable to carry out normal cellular reproductive function.
Antimetalobites include a diverse group of compounds which interfere with various metabolic processes, thereby disrupting normal cellular functions. These agents may act by two general mechanisms: By incorporating a drug, rather than a normal cellular constituent, into an essential chemical compound; or by inhibiting a key enzyme from functioning normally. Their primary benefit is the ability to disrupt nucleic acid synthesis. These agents work on dividing cells during the S phase of nucleic acid synthesis and are most effective on rapidly proliferating neoplasms.
There are also some hormones that are used to treat several types of neoplasms. Hormonal therapy interferes at a cellular membrane level with growth stimulatory receptor proteins.
Other antineoplastic agents include antibiotics. Antibiotic-type antineoplastic agents, unlike their antiinfective relatives, are capable of disrupting cellular function of hosts (mammalian) tissues. Their primary mechanism of action are to inhibit DNA-dependent RNA synthesis and to delay or inhibit mitosis.
Mitotic inhibitors are another type of antineoplastic agent. Some have a mechanism that inhibits DNA synthesis at specific phases of the cell cycle while others bind to tubulin, the subunits of the microtubules that form the mitotic spindle, thus causing metaphase arrests. Other mitotic inhibitors enhance the polymerization of tubulin and induces the production of stable, nonfunctional microtubules, thus inhibiting cell replication.
Some aspects of the subject inventions relate to the system and method of delivering such agents into the tissue of a living being through the use of the devices disclosed herein.
This invention includes various aspects. For example, there is provided a system and method for opening a lumen in an occluded blood vessel, e.g., a coronary bypass graft, of a living being""s vascular system located downstream of another blood vessel, e.g., the aorta, from which blood will flow to the occluded blood vessel. The system basically comprises a guide catheter, a lumen-opening catheter, a debris blocking member, and a fluid flow system.
The guide catheter has a distal end portion and at least one blood entrance port located proximally of the distal end portion. The lumen-opening catheter extends through the guide catheter to establish a fluid flow passageway therebetween and has a working head, e.g., a rotatable impacting member, for location immediately adjacent the occlusive material within the occluded blood vessel portion. The working head is arranged for operating on the occlusive material, e.g., repeatedly impacting it, to open a lumen for the freer flow of blood therethrough. Some debris may be produced by the operation of the working head.
The debris blocking member is located distally of the working head to prevent debris from flowing distally thereof.
The fluid flow system is arranged to introduce an infusate liquid at a first flow rate adjacent the working head and to withdraw that liquid through the passageway between the guide catheter and the lumen opening catheter at a second and higher flow rate to create a differential flow adjacent the working head, whereupon debris produced by the operation of the working head is withdrawn by the differential flow and flows with the liquid proximally through the passageway for extraction.
The blood entrance port in the distal end portion of the guide catheter is in communication with the passageway between the guide catheter and the lumen opening catheter, whereupon blood from the patent blood vessel portion may enter for merger with the liquid and debris flowing through that passageway.
In accordance with one preferred embodiment of this invention the debris blocking member is an inflatable balloon is provided at the distal end of the instrument to physically block the egress of any debris downstream of the apparatus. Perfusion means is preferably provided to inflate the balloon and to oxygenate downstream tissue when the balloon is inflated.
In accordance with another aspect of this invention an intra-luminal system is provided for locally delivering at least one beneficial agent to the wall of a lumen in the body of a living being. The system basically comprises at least one beneficial flowable agent, e.g., at least one antineoplastic agent, at least one anti-restenosis drug, at least one anti-proliferation drug, at least one lipid, etc., and a catheter. The catheter has a distal end portion including at least one outlet port. The at least one beneficial flowable agent is arranged to be controllably introduced through the catheter and out of the outlet port for localized delivery to the wall of the lumen wall.